chr11-2884919-C-A

Variant names:

• chr11-2884919-C-A
• rs1060500180
• NM_001122630.2:c.538G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122630.2(CDKN1C):​c.538G>T​(p.Ala180Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A180V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.953
• Publications: 0 publications found

Genes affected

CDKN1C (HGNC:1786): (cyclin dependent kinase inhibitor 1C) This gene is imprinted, with preferential expression of the maternal allele. The encoded protein is a tight-binding, strong inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation. Mutations in this gene are implicated in sporadic cancers and Beckwith-Wiedemann syndorome, suggesting that this gene is a tumor suppressor candidate. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]

CDKN1C Gene-Disease associations (from GenCC):

• Beckwith-Wiedemann syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• IMAGe syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, G2P, Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Beckwith-Wiedemann syndrome due to CDKN1C mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intrauterine growth restriction-short stature-early adult-onset diabetes syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Silver-Russell syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10004857).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122630.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.538G>T	p.Ala180Ser	missense	Exon 2 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.571G>T	p.Ala191Ser	missense	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.571G>T	p.Ala191Ser	missense	Exon 1 of 3	NP_001349403.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.538G>T	p.Ala180Ser	missense	Exon 2 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.571G>T	p.Ala191Ser	missense	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.571G>T	p.Ala191Ser	missense	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 60 AF XY: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 696564 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 329292

African (AFR) AF: 0.00 AC: 0 AN: 11740

American (AMR) AF: 0.00 AC: 0 AN: 3196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6446

East Asian (EAS) AF: 0.00 AC: 0 AN: 7772

South Asian (SAS) AF: 0.00 AC: 0 AN: 13828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1636

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 618378

Other (OTH) AF: 0.00 AC: 0 AN: 25040

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Beckwith-Wiedemann syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Benign	0.94
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.048	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.95
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.049
Sift	Benign	0.49	T
Sift4G	Uncertain	0.020	D
Polyphen		0.75	P
Vest4		0.085
MutPred		0.30		Gain of glycosylation at A191 (P = 0)
MVP		0.68
MPC		1.2
ClinPred		0.10	T
GERP RS		1.7
Varity_R		0.048
gMVP		0.065
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060500180; hg19: chr11-2906149;